Nitroimidazole hypoxic cell radiation sensitizers hold the potential to be of significant benefit in the treatment of human cancers. However a neurotoxic action expressed by these compounds has effectively eliminated the realization of this potential to date. Furthermore, it should be anticipated that this neurotoxic expression may continue to compromise the realization of the full protential of such compounds in the future. This is, of course, unless it becomes possible to more clearly understand how these compounds interact with nervous tissue in this manner. Misonidazole-induced neurotoxicity has been described as a "dying back" neuropathy or a Wallerian Degeneration. Examination of pathology from desmethylmisonidazole intoxicated animals tends to suggest that this may be an inadequate description of this neuropathy. The neuropathy produced by desmethylmisonidazole, when it develops, appears to carry a much stronger central nervous system involvement (than does misonidazole) and does not appear to be obviously suggestive of a "dying back" or a Wallerian neuropathy. This need not suggest that the two neuropathies are fundamentally different, but rather than a more general picture of the disorder is being obtained. Furthermore, our preliminary work with desmethylmisonidazole and misonidazole does suggest that these compounds may not be equally neurotoxic on a equimolar (brain) exposure basis. This would suggest that the relative neurotoxicities of 2-nitroimidazoles may not be entirely predictable by tissue distribution or bioavailability parameters. A hypothesis of this proposal is that brain damage is a direct result of nitroimidazole intoxication and that this encepalopathy is fundamental in elucidating basic mechanisms for damage. Detailed examination of brain pathology resulting from four different nitroimidazoles all indicate that the specific topography of brain lesions is identical to or nearly identical to the encepalopathy resulting from thiamine deprivation. Preliminary studies show that administration of thiamine and niacin prior to desmethylmisonidazole significantly delays the onset of neuropathy. Certain aspects of metabolism are discussed.